Accelerating pharmaceutical development part of 2015 AAPS session on: Fast to FIH versus Fast to Commercial: Paradigms, Trade-offs, and counter-balances

Rahul Rajan

Why accelerate process development? The patient is waiting…

• Development times are very long – typically 12-15 years

• Costs of drug development are high: e.g. $13-19M just to have drug for first in human

• Pressures exist on healthcare system and payers demand unambiguous value

• Need to accelerate process development, especially to test effect of drug on human biology (First in human introduction)

Aspects of pharmaceutical development covered in this presentation

Molecule

Selection

Drug

Substance

(API) process

development

Drug Product

Development

Manufacturing,

testing,

release,

stability

Pharmaceutical development has several inter-dependent workstreams…

CMC Activities for Development of MAbs By Susan Dana Jones, Patricia Seymour and Howard L. Levine

| April 5, 2010 Critical steps to reach IND with a therapeutic antibody - See more at:

http://www.contractpharma.com/issues/2010-04/view_features/cmc-activities-for-development-of-

mabs#sthash.SO9aprO8.dpuf

Example

Large molecule

Process development

timeline

Smart from the start: finding the right drug candidate for pharmaceutical development using predictive approaches • Traditional approach: detect

stability differences under accelerated conditions e.g. 40C

• Covalent modifications typically follow trends at higher temperatures

• Cases exist for inverse in aggregation trends for mAbs

• “pH jump” experiment can be used as a predictive tool to assess molecule behavior under physiological conditions (parenteral delivery)

Expose to pH 7, 37C

Candidate 1, 4C

Candidate 2, 4C

Candidate 2, 40C

Candidate 1, 40C

Accelerating pharmaceutical development when there are challenges: modeling approaches

• Arginine found to prevent protein aggregation

• Molecular dynamics simulations reveal

arginine cluster formation by head-to-tail

hydrogen bonding

• Interaction of arginine with aromatic and

charged side chains

• Arginine behaves as a “chemical chaperone”

Shukla D and Trout BL J.Phys.Chem. 2010, 114 (42), pp

13426–13438

Rajan RS, Tsumoto K, Tokunaga M, Tokunaga H, Kita Y,

Arakawa T.

Curr Med Chem. 2011;18(1):1-15

• Predicting the efficiency of human

intenstinal absorption using a “unity

model”

• Measure aqueous solubility (log Sw) and

octanol-water partition coefficient (log Kow)

• Using this calculate “maximum absorption

potential” values

• Correlation between MAP value and drugs

that are absorbed well (FA≥0.5) or poorly

absorbed (FA<0.5)

Patel, RB, Admire B, Yalkowsky SH Curr Drug Deliv.

2015;12(2):238-43.

Accelerating pharmaceutical development by means of technology investments

Clinical

New Clinical

Capabilities

Global Support

& Expansion

Technologies

The Drug Product Continuum: A transformational Network Solution to Product Commercialization and Life Cycle Management

Commercial

Formulation Dev

DP Commercial

Process Dev

Clinical DP

Manufacturing

Commercial DP

Manufacturing

Continuum of capabilities, data sharing, knowledge management and coordinated investments

ensures robust drug product commercialization and life cycle management

Drug Product

Pilot Facility

Engineering

Technology

Advancement &

Experimentation

Development / Engineering

New

Commercial

Capability

Improved

Current

Processes &

Global

Expansion

Capability

Commercial

Creating an end-to-end Drug Product facility to address pharmaceutical development challenges

9

How such a facility may be used to capture manufacturing stresses for formulation & DP process development

UF/DF Bulk Drug

Processing

Storage Filler Transportation Analytics

Small & medium

scale semi-

automated units

Process multiple

formulations

through “worst

case”

manufacturing

stresses

Increase

capacity

Introduce

representative

filler stress e.g.

time/pressure

filler

Subject product to

representative

transportation stress

High throughput

analytics especially

to analyze particles;

Higher

temperature to

enable high

concentration

formulations

Unit

operation/process

development

Facility will meet large

increase in demand for

this type of testing

Introduce new high-

throughput

capabilities; layer in

complexity in

automation

10

Accelerating formulation development: leverage miniaturization and automation

Buffer and Excipient Stock Solutions

Automated Formulation Preparation Systems

+

Stability storage, stresses

Analytical tests to evaluate

compatibility and stability

Accelerate development and reduce resources to identify stable formulations

through implementation of automated technologies

Statistical Design

of Experiments

Enhanced Data

Processing Capabilities

Automated Analytics

Accelerating process development: example of time savings by automation

• These are newly designed automated capabilities at Amgen

• They are designed to significantly expedite drug product development

Automated Capability

FTE hours to

test 1000

samples manually

FTE hours to

test 1000

samples w/ automation

Aliquotting 5 2.5

Sample prep for CE-SDS

42 21

Viscosity 300 8

Subvisible detection (HIAC)

50 3

pH 50 8

Absorption (UV-Vis)

80 5

Syringe to vial/plate transfer

8 2

Labeler 8 1.5

Machine vision 17 2

Subvisible detection (MFI)

400 30

Plate-based buffer exchange

400 48

For Internal Use Only. Amgen Confidential. 13

New commercial formulation development

paradigm

Rapidly screen formulation landscape

Directly integrate into pilot facility: in-depth

formulation and processability study

• High throughput capabilities

• Increased capacity to

process formulations

20 Formulation

Screening

3–5 Formulation Processability

CFR OLD

~1.5–2yrs ~10mo

≥ 9

6 F

orm

ula

tio

n

HT

Scre

enin

g

5–20 Formulation

Processability CFR NEW

Shortened timeline to CFR

Earlier, longer stability data

~3mo ~12mo

Accelerating pharmaceutical development: using automated workflows

• Automation was used to synthesize co-crystals in a 96-well plate

• Ability to sample a greater design space and more effectively do so

• Other examples include automating solid-phase synthesis

V. Luu et al, International Journal of

Pharmaceutics 441 (2013) 356– 364

Tan, Het al 2008. An integrated highthroughput screening approach for purification of solid organic compounds by titration and

crystallization in solvents. Org. Process Res. Dev. 12, 58–65.

Accelerating process development: use of platforms

• Platform: a collective body of knowledge translated into a consistent set of practices

• suit certain kinds of modalities e.g. mAbs

• Example of drug product process is shown here

• Platforms are not static but evolve with increasing knowledge

• Utilizing platforms = speed by avoiding redevelopment for each “similar” molecule

• Require integrated drug product design

• Formulation, process, container, device and related attribute control

Current Perspectives on Stability of Protein Drug Products during Formulation, Fill and Finish Operations

Nitin Rathore and Rahul Rajan, Biotechnology Prog. (2008) 24, 3, 504-514

Accelerating process development: change the paradigm (using pools instead of clones)

TIM

E

Accelerating pharmaceutical development: change the paradigm (continuous manufacturing)

Synthesis Crystallization Blending Granulation

&

Sizing

Tablet press

& coating

Test & Storage Test & Storage Test & Storage

Transport

Test & Tablets

Test & Storage

Region 1 Region 2 (Months)

Batch

Adapted from Lee, S.L et al J.Pharm.Innovation (2015) 10(3), 191-199

Synthesis Crystallization Blending Granulation

&

Sizing Tablets

Tablet press

& coating

PAT & Active process control systems (Days) Continuous

Paradigms for clinical and commercial pharmaceutical development

Discovery Preclinical Phase 1 Phase 2 Phase 3

Molecule

selection

Clinical

Pharmaceutical

development

Commercial

Pharmaceutical

development

Discovery Preclinical Phase 1 Phase 2

Molecule

selection

Clinical & commercial

Pharmaceutical

development

Discovery Preclinical Phase 1 Phase 2

Molecule

selection

Clinical & commercial

Pharmaceutical

development

Phase 3

Fast to Patient

Front Loading:

Single cycle

Front Loading:

reduced clinical development

In summary: approaches to accelerate process development

Modeling &

Predictive

Approaches

Automation

Platforms

Better

information

management

Acknowledgements

• Ping Yeh

• Arwinder Nagi

• Darren Reid

• Paco Alvarez

• Nitin Rathore

• Ranjini Ramachander

• Karthik Nagapudi

• Jason Tedrow

• Rohini Deshpande

• Dave Pecosky

• Vishal Nashine

• Ajit Narang

• Rajesh Gandhi

• Earl Dye

• David Le

• Judy Purtell

• Kim Westland

• Jeff Yeary

• Kevin Melford

• Cindy Ren